The renin-angiotensin system (RAS) plays a central role in the regulation of normal blood pressure and seems to be critically involved in hypertension development and maintenance as well as congestive heart failure. Angiotensin II (A II) is an octapeptide hormone produced mainly in the blood during the cleavage of angiotensin I by angiotensin converting enzyme (ACE) localized on the endothelium of blood vessels of lung, kidney, and many other organs. It is the end product of the renin-angiotensin system (RAS) and is a powerful arterial vasoconstrictor that exerts its action by interacting with specific receptors present on cell membranes. One of the possible modes of controlling the RAS is angiotensin II receptor antagonism. Several peptide analogs of A II are known to inhibit the effect of this hormone by competitively blocking the receptors, but their experimental and clinical applications have been limited by partial agonist activity and lack of oral absorption [M. Antonaccio. Clin. Exp. Hypertens. A4, 27-46 (1982); D. H. P. Streeten and G. H. Anderson, Jr. Handbook of Hypertension, Clinical Pharmacology of Antihypertensive Drugs, ed. A. E. Doyle, Vol. 5, pp. 246-271, Elsevier Science Publisher, Amsterdam, The Netherlands, 1984].
There are several reports of non-peptidic angiotensin-II antagonists, most of which are nitrogen heterocycles substituted on a nitrogen with a substituted biphenylmethyl group. Some of the heterocycles reported are imidazoles (EP 253,310), imidazopyridines (EP 400,974), quinazolinones (EP 411,766), triazoles (EP 409,332), triazolinones (EP 412,594) pyrimidinones (EP 419,048) and pyrazoles (WO 91/15479).
In addition EP 443,983 and EP 490,820 describe A-II antagonists which omit the heterocycles and are acyl or alkoxycarbonyl derivatives of biphenylmethylamines.